HIV-1 Vpr Triggers Natural Killer Cell–Mediated Lysis of Infected Cells through Activation of the ATR-Mediated DNA Damage Response

Jeffrey Ward,Erik Zimmerman,Jason Dehart,Enrico Brunetta,Zachary Davis,Alberto Bosque,Vicente Planelles,Domenico Mavilio,Edward Barker,Thomas J Hope

doi:10.1371/journal.ppat.1000613

Abstract

Natural killer (NK) cells are stimulated by ligands on virus-infected cells. We have recently demonstrated that NK cells respond to human immunodeficiency virus type-1 (HIV-1)-infected autologous T-cells, in part, through the recognition of ligands for the NK cell activating receptor NKG2D on the surface of the infected cells. Uninfected primary CD4pos T-cell blasts express little, if any, NKG2D ligands. In the present study we determined the mechanism through which ligands for NKG2D are induced on HIV-1-infected cells. Our studies reveal that expression of vpr is necessary and sufficient to elicit the expression of NKG2D ligands in the context of HIV-1 infection. Vpr specifically induces surface expression of the unique-long 16 binding proteins (ULBP)-1 and ULBP-2, but not ULBP-3, MHC class I-related chain molecules (MIC)-A or MIC-B. In these studies we also demonstrated that Vpr increases the level of ULBP-1 and ULBP-2 mRNA in primary CD4pos T-cell blasts. The presence of ULBP-1 and ULBP-2 on HIV-1 infected cells is dependent on the ability of Vpr to associate with a protein complex know as Cullin 4a (Cul4a)/damaged DNA binding protein 1 (DDB1) and Cul4a-associated factor-1(DCAF-1) E3 ubiquitin ligase (Cul4aDCAF-1). ULBP-1 and -2 expression by Vpr is also dependent on activation of the DNA damage sensor, ataxia telangiectasia and rad-3-related kinase (ATR). When T-cell blasts are infected with a vpr-deficient HIV-1, NK cells are impaired in killing the infected cells. Thus, HIV-1 Vpr actively triggers the expression of the ligands to the NK cell activation receptor.

Highlights

Natural killer (NK) cells are involved in the immune response against tumor cells and virus-infected cells without the requirement for previous exposure to their targets or their products
We demonstrated that ligands for the NK cell activation receptor, NKG2D, trigger NK cell-mediated response to infected cells
Despite the observation that NKG2D ligands are expressed on infected cells, it is unclear how human immunodeficiency virus type-1 (HIV-1) induces their expression

Summary

Introduction

NK cells are involved in the immune response against tumor cells and virus-infected cells without the requirement for previous exposure to their targets or their products. The importance of NK cells in restraining viral infection was first shown in studies using murine models in which NK cells were depleted [1,2,3]. Lack of NK cells in humans or defects in NK cell function are associated with fatal disseminated herpes virus infection [8,9,10,11,12,13]. Direct target cell killing by NK cells is mediated by the regulated release of granules containing perforin and granzymes [14,15]. The granzymes most likely enter the target cell through perforin-formed channels [17] or endocytosis [16] and induce apoptosis of the infected cells. CD56bright NK cells express less perforin than CD56dim NK cells but higher concentrations of cytokines and as such are important in regulating immune responses

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Conclusion